Relationship of XIST expression and responses of ovarian cancer to chemotherapy

Expression profiling to characterize cancer pharmacology has become a new approach to discover novel molecular targets for prognostic markers and cancer therapy. In a study to compare the global RNA expression profiles between primary and recurrent ovarian tumors from the same patient, we have identified XIST (inactive X chromosome-specific transcripts) as the most differentially expressed gene that was down-regulated in the recurrent tumor. XIST encodes a spliced noncoding polyadenylated transcript that is unique in being expressed exclusively from the inactive X chromosome and is involved in the X-inactivation process. Subsequent characterization of XIST expression in a panel of female cancer cell lines showed that the expression level of XIST correlates significantly with Taxol sensitivity. The clinical relevance of this observation is demonstrated by the strong association between XIST RNA levels and disease-free periods of ovarian cancer patients in a group of 21 ovarian cancer cases with Taxol in the therapeutic regiments. Cytogenetic studies on ovarian cancer cell lines indicated that loss of inactive X chromosome is one mechanism for the loss of XIST transcripts in the cell lines. Our data suggest that XIST expression may be a potential marker for chemotherapeutic responses in ovarian cancer.

Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS)

Background Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening. Methods We did a prospective multicentre cohort study in 649 women aged 35-49 years with a strong family history of breast cancer or a high probability of a BRCA1, BRCA2, or TP53 mutation. We recruited participants from 22 centres in the UK, and offered the women annual screening with CE MRI and mammography for 2-7 years. Findings We diagnosed 35 cancers in the 649 women screened with both mammography and CE MRI (1881 screens): 19 by CE MRI only, six by mammography only, and eight by both, with two interval cases. Sensitivity was significantly higher for CE MRI (77%, 95% CI 60-90) than for mammography (40%, 24-58; p=0.01), and was 94% (81-99) when both methods were used. Specificity was 93% (92-95) for mammography, 81% (80-83) for CE MRI (p

A Test of Performance of Breast MRI Interpretation in a Multicentre Screening Study

Objectives: The aim of this study was to assess the consistency and performance of radiologists interpreting breast magnetic resonance imaging (MRI) examinations. Materials and Methods: Two test sets of eight cases comprising cancers, benign disease, technical problems and parenchymal enhancement were prepared from two manufacturers' equipment (X and Y) and reported by 15 radiologists using the recording form and scoring system of the UK MRI breast screening study [(MAgnetic Resonance Imaging in Breast Screening (MARIBS)]. Variations in assessments of morphology, kinetic scores and diagnosis were measured by assessing intraobserver and interobserver variability and agreement. The sensitivity and specificity of reporting performances was determined using receiver operating characteristic (ROC) curve analysis. Results: Intraobserver variation was seen in 13 (27.7%) of 47 of the radiologists' conclusions (four technical and seven pathological differences). Substantial interobserver variation was observed in the scores recorded for morphology, pattern of enhancement, quantification of enhancement and washout pattern. The overall sensitivity of breast MRI was high [88.6%, 95% confidence interval (CI) 77.4-94.7%], combined with a specificity of 69.2% (95% CI 60.5-76.7%). The sensitivities were similar for the two test sets (P=.3), but the specificity was significantly higher for the Manufacturer X dataset (P

A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells

Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G(2)-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.

Interpretation of the temperature dependence of equilibrium and rate constants

The objective of this review is to draw attention to potential pitfalls in attempts to glean mechanistic information from the magnitudes of standard enthalpies and entropies derived from the temperature dependence of equilibrium and rate constants for protein interactions. Problems arise because the minimalist model that suffices to describe the energy differences between initial and final states usually comprises a set of linked equilibria, each of which is characterized by its own energetics. For example, because the overall standard enthalpy is a composite of those individual values, a positive magnitude for AHO can still arise despite all reactions within the subset being characterized by negative enthalpy changes: designation of the reaction as being entropy driven is thus equivocal. An experimenter must always bear in mind the fact that any mechanistic interpretation of the magnitudes of thermodynamic parameters refers to the reaction model rather than the experimental system For the same reason there is little point in subjecting the temperature dependence of rate constants for protein interactions to transition-state analysis. If comparisons with reported values of standard enthalpy and entropy of activation are needed, they are readily calculated from the empirical Arrhenius parameters. Copyright (c) 2006 John Wiley & Sons, Ltd.

Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGF beta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF beta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf beta 1 nail murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF beta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gamma H2AX radiation-induced foci; and increased radiosensitivity compared with TGF beta competent cells. We determined that loss of TGF beta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF beta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf beta 1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF beta may be used to advantage in cancer therapy.